Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

Abstract

Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.

Chromium VI − Induced developmental toxicity of placenta is mediated through spatiotemporal dysregulation of cell survival and apoptotic proteins

“…Preeclampsia and IUGR are disorders that are rooted in defects of placental development [67]. The current study shows that CrVI induces toxic lesions in the LZ and BZ of the placenta.…”

Preterm prelabor rupture of the membranes: A disease of the fetal membranes

“…The pregnant uterine environment, especially fetal tissues (ie placenta), progress through various states of oxidative status as the fetus matures 95-98 . Fetal and placental growth are linked to changing status of oxygen tension and OS in response to various oxidative conditions.…”

Adjunctive Use of Esomeprazole in the Treatment of Pre-Eclampsia: A Case Report and Literature Review

“…The mitochondrial complex I inhibitor, metformina and the cholesterol-lowering agent, pravastatin, down-regulate sFLT-I/PIGF ratio, [83][84] but may not be recommended until more trials due to the uncertain effects of mTOR inhibitors on pregnancy outcomes, especially in first trimester. [85][86] [87] This may be more important in Africa where lack of nutrients stir up pathogenesis of placental malaria which negatively impacts fetal growth by further downregulating mTOR signalling pathways which link growth factors, insulin, IGF-I and VEGF in nutrient supply to fetus. [88] Similar to metformin, esomeprazole activates AMPK and inhibits mTOR necessary for optimal autophagy induction via hypoxia-inducible factor-Iα, a survival mechanism necessary to maintain pregnancy.…”